A growing body of evidence suggests that a relatively rare subset of cells within a cancer subverts properties normally ascribed to stem cells in regenerating tissues, such as enhanced self-renewal and survival capacity, which render these cancer stem cells (CSC) resistant to treatments that target rapidly dividing cells (Visvader, J. E. Nature 469, 314-322 (2011); Guzman, M. L., et al. Proc Natl Acad Sci USA 99, 16220-16225 (2002).
Chronic Myeloid Leukemia (CML) progresses from early, Chronic Phase (CP) to the more advanced Blast Crisis (BC) stage. With progression to blast crisis (BC), CML stem cells become more resistant to therapies targeting BCR-ABL. As BCR-ABL targeted therapy initiates apoptosis, these results suggest that CML CSC may become increasingly resistant to apoptosis with progression. B-cell lymphoma-2 (Bcl-2, or BCL2) family isoform expression is a critical player in the progression from CP to BC.
The BCL2 family is comprised of a diverse set of genes that integrate pro-survival and pro-death stimuli and modulate the permeability of the mitochondrial membrane (Reed, J. C. Blood 111, 3322-3330 (2008)). Activation of mitochondrial outer membrane permeability (MOMP) results in activation of a caspase cascade triggering apoptosis. Pro-survival BCL2 family genes contribute to leukemogenesis (Beverly, L. J. & Varmus, H. E. Oncogene 28, 1274-1279 (2009)), CML progression, TKI resistance (Jaiswal, S. et al. cited above; Sanchez-Garcia, I. & Grutz, G., Proc Natl Acad Sci USA 92, 5287-5291 (1995); Horita, M., et al. J Exp Med 191, 977-984 (2000); Aichberger, K. J., et al. Blood 105, 3303-3311 (2005); Konopleva, M., et al. Br J Haematol 118, 521-534 (2002) and hematopoietic stem and progenitor cell survival (Milyaysky, M., et al. Cell Stem Cell 7, 186-197 (2010); Domen, J. & Weissman, I. L. Exp Hematol 31, 631-639 (2003)) by direct inhibition of MOMP.
Existing methods for predicting leukemia progression and drug susceptibility analyze the bulk of cells from a leukemia and do not quantitate BCL2 family molecules. However, not all cells in a leukemia are equivalent and CSC in particular display aberrant expression of BCL2 molecules. Because CSC drive the progression of leukemia, analysis and characterization of that population specifically could allow for better prediction of the course of the disease.
CSC in bone and bone marrow niches are especially resistant to treatment. This may be due to increased quiescence (exit from the cell cycle) of CSC in the niche as well as increased survival related to aberrant ratios of BCL2 family isoforms.